Health Effects of Penitrem A – Tremorgenic Issues

 

 

This page lists medical journal articles discussing the association between tremorgenic issues and the mycotoxin known as penitrem A.

The Health Effects of Penitrem A page of the Paradigm Change site provides further information on the effects of this mycotoxin.

 

Edwards G., Weston A. H.. The role of potassium channels in excitable cells. Diabetes research and clinical practice. 1995;28 Suppl. PMID: 8529520

Potassium (K) channels regulate cellular excitability. Their opening hyperpolarises the membrane potential and induces quiescence whereas their closure produces depolarisation and excitation. K-channel modulators are important in determining channel function. These include drugs like tetraethylammonium and 4-aminopyridine and more recently-discovered selective agents active at KATP and BKCa. These are typified by diazoxide, levcromakalim and glibenclamide and by NS1619, iberiotoxin and penitrem A, respectively.

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Knaus H. G., McManus O. B., Lee S. H., et al. Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry. 1994;33:5819–5828. PMID: 7514038

Tremorgenic indole alkaloids produce neurological disorders (e.g., staggers syndromes) in ruminants. The mode of action of these fungal mycotoxins is not understood but may be related to their known effects on neurotransmitter release. To determine whether these effects could be due to inhibition of K+ channels, the interaction of various indole diterpenes with high-conductance Ca(2+)-activated K+ (maxi-K) channels was examined. Paspalitrem A, paspalitrem C, aflatrem, penitrem A, and paspalinine inhibit binding of [125I]charybdotoxin (ChTX) to maxi-K channels in bovine aortic smooth muscle sarcolemmal membranes. Taken together, these data suggest that indole diterpenes are the most potent nonpeptidyl inhibitors of maxi-K channels identified to date. Some of their pharmacological properties could be explained by inhibition of maxi-K channels, although tremorgenicity may be unrelated to channel block.

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Edwards G., Niederste-Hollenberg A., Schneider J., Noack T., Weston A. H.. Ion channel modulation by NS 1619, the putative BKCa channel opener, in vascular smooth muscle. British journal of pharmacology. 1994;113:1538–1547. PMID: 7534190 

The effects of NS 1619, the putative BKCa channel opener, were investigated on rat intact portal veins and on single smooth muscle cells enzymatically separated from the same tissue. The stimulation of outward currents by NS 1619 at -10 mV was independent of the presence of Ca2+ in the bath or pipette solutions but was antagonized by either charybdotoxin (250 nM) or penitrem A (100 nM) in the bath solution.

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Selala M. I., Laekeman G. M., Loenders B., Musuku A., Herman A. G., Schepens P.. In vitro effects of tremorgenic mycotoxins. Journal of natural products. 1991;54:207–212. PMID: 2045816

Paxilline was isolated from Penicillium paxilli (NRRL 6110). It was studied together with penitrem B and verruculogen in the electrically stimulated guinea pig ileum. All three mycotoxins enhanced the electrically induced twitch contractions, without influencing the contractions provoked by exogenous acetylcholine. The effect of the mycotoxins could be greatly diminished by hyoscine. The possible mechanism of action of these substances in this in vitro model is discussed. The electrically stimulated guinea pig ileum could be useful in the detection and estimation of the biological activity of tremorgenic mycotoxins.

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Jortner B. S., Ehrich M., Katherman A. E., Huckle W. R., Carter M. E.. Effects of prolonged tremor due to penitrem A in mice. Drug and chemical toxicology. 1986;9:101–116. PMID: 3757822 

Adult mice were given subcutaneous injections of purified penitrem A (10 mg/kg) dissolved in corn oil. The mycotoxin was prepared by ether extraction and absorption chromatography; identity was established by absorption and mass spectra. Tremors were sustained for 72 hr following a single dose; readministration every 3 days was used to provide continuous trembling for 18 days. No lesions specifically attributed to penitrem A could be detected by histological examination of brains even after 18 days of trembling. Pharmacological agents affecting central nervous system neurotransmitters had some capacity to modify the effects of penitrem A.

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Peterson D. W., Penny R. H., Day J. B., Mantle P. G.. A comparative study of sheep and pigs given the tremorgenic mycotoxins verruculogen and penitrem A. Research in veterinary science. 1982;33:183–187. PMID: 7146626

The moulds Penicillium simplicissimum and P crustosum and the tremorgenic mycotoxinsverruculogen and penitrem A, were given to sheep and pigs to compare their potencies. Pigs were generally less susceptible and in both species penitrem A was less potent than verruculogen. Long and short acting barbiturate anaesthesia blocked the effects of lethal doses of tremorgens. Sedation with diazepam diminished, but did not block, mycotoxin-induced tremors suggesting that there was no specific action of this anticonvulsant sedative on tremorgens.

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Kyriakidis N., Waight E. S., Day J. B., Mantle P. G.. Novel metabolites from Penicillium crustosum, including penitrem E, a tremorgenic mycotoxin. Applied and environmental microbiology. 1981;42:61–62. PMID: 7259165 

Two new indolic metabolites were isolated from Penicillium crustosum and separated from other penitrem mycotoxins by high-performance liquid chromatography. Penitrem D is a deoxy-penitrem A. Penitrem E is dechloro-penitrem A and was shown to be tremorgenic in mice, although it has only one-third of the activity of penitrem A. Roquefortine was also shown, for the first time, to be an important metabolic product of P. crustosum.

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Penny R. H., OʼSullivan B. M., Mantle P. G., Shaw B. I.. Clinical studies on tremorgenic mycotoxicoses in sheep. The Veterinary record. 1979;105:392–393. PMID: 552734

The clinical responses of sheep dosed orally over seven to 14 weeks with the dried mycelium of a soil-borne mould containing the tremorgenic mycotoxin penitrem A are described. An initial tremoring response was  overshadowed by an incoordination syndrome similar to that seen in ryegrass staggers. In spite of protracted staggers symptomatology, correlated with in vitro changes in the release of neurotransmitter amino acids from corpus striatum nerve ending preparations, no histopathology was evident in the wide range of neural and other tissue studied.

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Patterson D. S., Roberts B. A., Shreeve B. J., MacDonald S. M., Hayes A. W.. Tremorgenic toxins produced by soil fungi. Applied and environmental microbiology. 1979;37:172–173. PMID: 760635 

Penitrem A or an unknown tremorgenic toxin, “X,” was produced by 10 of 60 fungal isolates obtained from a pasture involved in an outbreak in cattle and sheep resembling migram and ryegrass staggers. Tremorgenic properties of extracts containing penitrem A or toxin X were confirmed by bioassay.

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Mantle P. G., Mortimer P. H., White E. P.. Mycotoxic tremorgens of Claviceps paspali and Penicillium cyclopium: a comparative study of effects on sheep and cattle in relation to natural staggers syndromes. Research in veterinary science. 1978;24:49–56. PMID: 625600

Claviceps paspali sclerotia were dosed orally at various levels to sheep and cattle and the neurotoxic effects are described. Evidence is presented which indicates that the tremors are produced by a neutral tremorgen fraction. The mixture of C paspali tremorgens has not been separated and characterised but its components are chemically related to other known tremorgens, such as penitrem A, produced by saprophytic moulds, notably Penicillium cyclopium. P cyclopium mycelium and C paspali sclerotia were dosed to produce comparable effects in sheep and in cattle. Similarly, effects of penitrem A and tremorgen concentrate of C paspali were compared after intravenous dosage to sheep. Observed enurotoxic effects of both moulds were identical in most respects. A low level of tremorgenic activity was detected at the honeydew stage of C paspali. These findings are discussed in relation to staggers syndromes occurring in grazing livestock.

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Hayes A. W., Hood R. D.. Effects of prenatal administration of penicillic acid and penitrem A to mice. Toxicon. 1978;16:92–96. PMID: 414379

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Wilson B. J., Hoekman T., Dettbarn W. D.. Effects of a fungus tremorgenic toxin (penitrem A) on transmission in rat phrenic nerve-diaphragm preparations. Brain research. 1972;40:540–544. PMID: 4337445

 

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